tbuckley/cabot-search huggingface dataset:
Abstract P3003: Endothelial-Specific Expression Of Cidec Improves High-Fat Diet-induced Vascular And Metabolic Dysfunction
Authors: Bijinu Balakrishnan, Abhishek Gupta, Vishva M Sharma, Mark Slayton, Kailey Gentner, Shakun Karki, Harrison Muturi, Sonia M Najjar, Analia S Loria, Noyan Gokce, Vishwajeet Puri
Journal: Circulation Research (2022)

Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), originally identified to be a lipid-droplet associated protein in adipocytes, positively associates with insulin sensitivity. Recently, we discovered that it is expressed abundantly in human endothelial cells (ECs) and regulates vascular function in obesity. The present study was designed to characterize the physiological effects and molecular actions of endothelial CIDEC in the control of vascular phenotype and whole-body glucose homeostasis. To achieve this, we generated a humanized mouse model expressing endothelial-specific human CIDEC (E-CIDECtg). E-CIDECtg mice exhibited protection against HFD-impaired glucose intolerance, insulin resistance and dyslipidemia. Moreover, these mice displayed improved insulin signaling and eNOS activation, enhanced endothelium-dependent vascular relaxation and improved vascularization of adipose tissue, skeletal muscle, and heart. Mechanistically, we identified a novel interplay of CIDEC-VEGFA-VEGFR2 that reduced VEGFA and VEGFR2 ubiquitin-mediated degradation thereby increasing VEGFR2 activation. Overall, our results demonstrate a protective role of endothelial CIDEC against obesity-induced metabolic and vascular dysfunction, in part, by modulation of VEGF signaling. These data suggests that CIDEC may be considered as a potential future therapeutic target for mitigating obesity-related cardiometabolic disease.
Abstract P1021: Translational Landscape Of Direct Cardiac Reprogramming Reveals A Role Of Ybx1 In Repressing Cardiac Fate Acquisition
Authors: Yifang Xie, Yuchen Yang, Jiandong Liu, Li Qian
Journal: Circulation Research (2022)

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds great promise for heart regeneration. Although great progress has been made in understanding the transcriptional and epigenetic mechanisms of iCM reprogramming, its translational regulation remains largely unexplored. Through integrative ribosome and transcriptomic profiling, we characterized the translational landscape of iCM reprogramming, and found extensive translatome repatterning during fibroblast conversion into iCM. Loss of function screening for translational regulators uncovered Ybx1 as a critical barrier to iCM induction. Knockdown of Ybx1 dramatically improved the efficiency and quality of iCM reprogramming. Mechanistically, depletion of Ybx1 de-repressed the translation of its direct targets Srf and Baf60c , both of which mediated, at least partially, the effect of Ybx1 depletion on iCM generation. Interestingly, upon removing Ybx1, Tbx5 alone could reprogram fibroblasts into iCMs that exhibit classic iCM molecular features and reprogramming trajectories revealed by our single cell dual-omics. In summary, we elucidated the translatome dynamics of iCM reprogramming and identified Ybx1 as a critical translational barrier to iCM generation, removing of which allowed single factor mediated iCM reprogramming.
The ERJ two years later
Authors: P Vermeire
Journal: European Respiratory Journal (1993)

The European Respiratory Journal (ERJ) now enters its s ix th year of publication.and its third year as orficial journal o f the European Respiratory Society (ERS ).Two years ago WC presented :1 programme [l] to el>lablish rhe ERJ as a lending journul covering all aspects of respiratory medicine and science, and serving as a platform for scientific interchange between the members of the growing community of physicians and researchers with interest in pulmonary medicine in Europe and abroad.It seems appropriate to review the progress made in reaching these goals.The journal continues tu strive hard to publish good original contributio ns related to both ex perimenwl and c linical research.as well as instruc ti ve clinical observations.We wish to maintain a good balance between both types of manuscript, to retain the interest of both the basic researcher and the clinician.We appreciate how sti ll more authors from all over the world allow us to review their best work for publication.We expect to receive 30% more manuscripts in 1992 than two years ago.Despite this higher workload our Associate Editors and numerous anonymous reviewers have managed to significantly reduce the mean "verdict time" between receipt of manuscripts and either notification of rejection or request for revision.In order to assist authors as much as possible in writing up their work, we have revised our Instructions to authors published in the back of each issue.For research papers, we now emphasise the need to state clearly the question they are intending to answer, as well its answer.We are grateful to Mrs Mimi Zeiger for her valuable cooperation in revising these instructions,
Abstract P1022: Intravenously Transplanted Mesenchymal Stem Cells--- A New Endocrine Reservoir For Cardioprotection
Authors: Anan Huang, Yue Liu, Xin Qi, Liping Wei, Shang Chen, Haoyan Huang, Jun Zhang, Zongjin Li
Journal: Circulation Research (2022)

Aims: Intravenous mesenchymal stem cells (MSCs) confer considerable cardiovascular benefits to patients. The lung, but not the heart, is the main trapped site for intravenous MSCs. It remains unclear how intravenous MSCs bridge this spatial gap between the lung and the heart to achieve cardiac repair. To investigate how intravenous MSCs, like an endocrine reservoir, secrete specific miRNA-enriched extracellular vesicles (EVs) gradually and continuously to alleviate doxorubicin (Dox)-induced cardiotoxicity. Methods and results: MSCs were isolated from human placenta tissue, and multiple molecular imaging was generated by modifying MSCs-DF or MSCs-Gluc transduced with firefly luciferase ( Fluc ) / enhanced green fluorescence protein (eGFP) or Gaussia luciferase (Gluc) lactadherin fusion protein. The Dox-induced cardiotoxicity murine model was constructed and an equal sum of MSCs was infused into mice by single high dose (5 х 10 6 MSCs) or repeated low dose (1 х 10 6 MSCs, 5 times) intravenously. Dox-induced cardiotoxicity, characterized by cardiac atrophy, left ventricular dysfunction, and injured myocardium, was alleviated by low doses of repeated MSCs. These cardioprotective effects were attributed to the suppression of GRP78 triggering stress-induced apoptosis of the endoplasmic reticulum (ER) in cardiomyocytes. Our results confirmed that miR-181a-5p in EVs derived from MSCs (MSC-EVs) inhibited GRP78. Intravenous MSCs-DF were trapped in the lung vasculature, secreted EVs into serum, which was confirmed by the detection of eGFP + EVs. Gluc activity increased in serum EVs from mice administrated with MSCs-Gluc. MiR-181a-5p, which inhibits GRP78 with high efficacy, expressed an increase in serum EVs and myocardium after injecting repeated low-dose MSCs. Up-regulation or down-regulation of miR-181a-5p levels in MSC-EVs had enhanced or weakened therapeutic effects on Dox-induced cardiotoxicity by modulating ER stress-induced apoptosis. Conclusion: This study identifies intravenous MSCs, recognized as an endocrine reservoir, secrete EVs enriched with miR-181a-5p in the blood to confer indirect cardioprotection against Dox-induced cardiotoxicity.
Abstract P3057: Heat Shock Protein Is Involved In Gja1-20k Transport To Mitochondria
Authors: Daisuke Shimura, Tingting Hong, Robin M Shaw
Journal: Circulation Research (2022)

GJA1-20k is an internally translated, N-terminus truncated isoform of the gap junction protein Connexin 43 (Cx43). We have identified essential roles of GJA1-20k for Cx43 trafficking to cell membrane, actin stabilization, and regulation of mitochondrial dynamics. Recently, we found that GJA1-20k works with actin to induce a “protective” mitochondrial fission, protecting cells and hearts against ischemia-reperfusion (I/R) injury. This GJA1-20k mediated mitochondrial fission does not require the canonical fission mediator, Dynamin-Related Protein 1 (DRP1) pathway. At present, however, little is known how GJA1-20k occurs at mitochondrial membrane. Our in silico analysis indicates that the N-terminus of GJA1-20k contains a potent binding site to Heat Shock Protein 70 (HSP70). Since HSP70 is a well known mitochondrial transporter, we hypothesized that HSP70 interacts with GJA1-20k to support its translocation to mitochondria. To explore the involvement of HSP70, in HeLa cells we knocked down HSP70 in the presence of exogenous GJA1-20k. An absence of HSP70 inhibited GJA1-20k localization to mitochondrial membrane. In fact, in the absence of HSP70, most GJA1-20k was aggregated, suggesting a failure to distribute. Given that the expression of both HSP70 and GJA1-20k are upregulated during I/R injury, these data indicate that both stress-response proteins cooperate to localize GJA1-20k to mitochondrial membrane, initiating protective mitochondrial fission.
Abstract P2069: In Vivo Investigation Of The Mechanisms Regulating Truncated Dystrophin Protein Turnover In The Heart
Authors: Addeli Bez Batti Angulski Spies, John Bauer, Joseph M Metzger
Journal: Circulation Research (2022)

Numerous inherited and acquired cardiac diseases are directly linked to a deficiency in the protein dystrophin, such as the development of severe cardiomyopathy in Duchenne Muscular Dystrophy (DMD) patients. Dilated cardiomyopathy, arrhythmias, and congestive heart failure represent the most important life-limiting condition in DMD. Currently, there is great excitement in the muscular dystrophy community as multiple ongoing gene-based therapies, are advancing through clinical trials. These therapies utilize miniaturized dystrophin constructs, and these modified dystrophins are the focus of this study. We implemented an innovative and valuable system to determine the direct physiological significance of dystrophin protein deficiency including determining the half-life of truncated dystrophin constructs. This system provides a novel means to investigate mechanistically how deletions in dystrophin affect therapeutically shortened dystrophin turnover in cardiac muscle in vivo. We used a floxed allele approach together with a cardiac directed (αMHC Mer-Cre-Mer) inducible Cre for precise control of full-length dystrophin or therapeutic micro-dystrophin gene excision. We examined the time course of full-length and micro-dystrophin mRNA as a biologically relevant surrogate for intact gene excision efficiency. Our data showed evidence of significant full-length dystrophin cDNA and micro-dystrophin gene excision, with a complete loss of micro-dystrophin mRNA and a gene excision efficiency of 80% for full-length dystrophin. Heart tissues were then extracted for protein quantitative analysis of micro-dystrophin (5, 10 and 30 days) and of full-length dystrophin (1, 3 and 6 months) post tamoxifen administration. Results reported a fast turnover rate for micro-dystrophin in the heart, with calculated half-life of between 5-7 days. In marked contrast, full-length dystrophin was highly stable with dystrophin protein content (~ 40%) at 6 months, after dystrophin gene excision. Studies of in vivo full-length and micro-dystrophin protein half-life in skeletal muscle, are ongoing. This work will provide key information required for long-term success of ongoing and future DMD therapies featuring gene therapy with shortened dystrophins.
Abstract P2101: Time Dependence Of Esophageal Injury With And Without Proactive Cooling During High-power Short-duration Radiofrequency Ablation
Authors: Marcela Mercado-Montoya, Tatiana Gomez-Bustamante, Erik B Kulstad, Enrique Berjano, Steven R Mickelsen, Pablo Hernandez-Arango, Jay Schieber, James D Daniels
Journal: Circulation Research (2022)

Background: Recent data suggest that luminal esophageal temperature (LET) monitoring during high-power short-duration (HPSD) ablation may be inadequate to prevent esophageal thermal injury during radiofrequency (RF) ablation. This is due in part to delayed responses to thermal latency and the continued temperature rise that occurs in tissues even after the cessation of RF energy with HPSD settings. Proactive esophageal cooling has been shown to reduce severe esophageal thermal injury during medium-power medium-duration RF ablation, but less is known about the effects in HPSD ablation. Objective: We aimed to quantify the time course of esophageal damage in scenarios with and without proactive esophageal cooling, hypothesizing a reduction in the resulting tissue damage with proactive esophageal cooling. Methods: Using a computer model of RF ablation in the left atrium adjacent to the esophagus, we calculated temperature over time using ablation power of 50 W for 10 s and 90 W for 4 s. We then determined the fraction of resulting damage to esophageal tissue via the Arrhenius equation and by the percentage of tissue above lethal isotherm temperature of 50°C. Transmurality of injury was then plotted over time, and results were compared between ablation with and without proactive esophageal cooling. Results: Esophageal damage increased even after the cessation of RF energy, suggesting significant thermal latency effects under HPSD ablation. Lesion growth continued for &gt;10 s after cessation of 50 W ablation energy, and for &gt;12 s after cessation of 90 W ablation energy without cooling. With proactive cooling, lesion growth after cessation of ablation energy was essentially halted. Without esophageal cooling, maximum injury transmurality reached 79% with 50 W, and 58% with 90 W. With esophageal cooling, injury transmurality remained below 20% with 50 W, and 10% with 90 W, representing reductions of 75% and 83%, respectively. Conclusions: RF ablation using HPSD settings demonstrates significant latency of effect, with tissue damage and lesion growth continuing beyond the cessation of application of RF energy. Proactive esophageal cooling significantly dampens this effect, reducing esophageal injury by up to 83%.
Abstract P1046: An Oxygen Gradient Microphysiological System To Model The Myocardial Infarct Border Zone
Authors: Megan L Rexius-Hall, Natalie N Khalil, Sean S Escopete, Xin Li, Jiayi Hu, Hongyan Yuan, Sarah Parker, Megan L McCain
Journal: Circulation Research (2022)

After a myocardial infarction, the border zone is characterized by an oxygen (O 2 ) gradient located at the interface between the injured, hypoxic cardiac tissue and adjacent normoxic, viable tissue. Yet, the impact of an O 2 gradient on cardiac function is not well understood because there is a lack of in vitro experimental platforms for generating such biomimetic O 2 landscapes. This unmet need has prevented systematic investigation into how hypoxic-normoxic intercellular communication affects cardiac function. In this study, a microphysiological system was engineered to generate and expose engineered cardiac tissues to a stable O 2 gradient as a “Border-Zone-on-a-Chip” model. Briefly, a microfluidic gas supply channel network was overlaid with a thin, gas-permeable polydimethylsiloxane membrane on which engineered cardiac tissue composed of neonatal rat ventricular myocytes was cultured. Constant perfusion of compressed gases through separate microfluidic channels and rapid diffusion of the gas conditions across the thin membrane produced an O 2 gradient. Functional and transcriptomic analysis revealed biological responses were uniquely regulated by an O 2 gradient when compared to engineered tissues exposed to global, homogeneous O 2 levels. In the gradient, there was a significant increase in the calcium transient time to peak (85%, p=0.0007) and tau time constant of decay (49%, p=0.006). There was a significant decrease in the longitudinal calcium wave propagation velocity (35%, p=0.03), diastolic stress (47%, p=0.01), and peak systolic stress (47%, p=0.01). Overall, the gradient exhibited hallmarks of arrhythmogenesis, hypocontractility, and activation of inflammation after 4 h of O 2 modulation. Importantly, these changes were distinct from those observed in tissues exposed to uniform normoxia or hypoxia, demonstrating distinct regulation of cardiac tissue phenotypes by an O 2 gradient. Studies are ongoing to elucidate a possible paracrine mechanism involved in the observed effects. By gaining functional and mechanistic insight into intercellular communication activated in O 2 gradients, microphysiological systems can direct future therapeutic strategies aimed at minimizing or preventing cardiac hypoxic injury.
Abstract P1116: Genetic Mapping Of Cardiomyocyte Ploidy Phenotypes To Identify Genetic Determinants Of Outcomes After Infarction
Authors: Alexandra L Purdy, Mary E Kolell, Makenna Knas, Santiago Alvarez, Parker Foster, Melinda R Dwinell, Laura M Saba, Caitlin O'Meara, Michaela Patterson
Journal: Circulation Research (2022)

Outcomes following cardiac injury are influenced by lifestyle and environment, as well as genetic background. Our interest lies in the latter, where very few genes have successfully been linked to heart failure. Contributors to this low success rate include high genetic diversity of patient populations, inability to control for non-genetic factors, and cellular complexities that contribute to outcomes. We propose utilizing the Hybrid Rat Diversity Panel (HRDP) to assess high throughput surrogate phenotypes, which can be predictive of outcomes after injury when measured in the basal state. This approach can offer a solution to the limitations of association studies for complex diseases like heart failure. Our surrogate phenotype of interest is cardiomyocyte ploidy, where high frequency of diploid cardiomyocytes is predictive of ability to regenerate and functional recovery. Conversely, an increased proportion of polyploid (≥8N) cardiomyocytes is associated with adverse ventricular remodeling and dilated cardiomyopathy. Having analyzed 50 of the 96 strains, we see that frequency of the MNDCMs varies from 1.3-20.3% across strains, while frequency of the highly polyploid CMs (≥8N) varies from 0.8-20.9%. Four strains have been selected for myocardial infarction (MI) studies, including M520 (17.4%) and F344 (20.3%) with high MNDCM content and GK (2.8%) and HXB23 (1.8%) with low MNDCM content. Following MI, both M520 and F344 rats exhibit a higher percentage of BrdU+ cardiomyocytes in the border zone region compared to HXB23 rats, supporting the hypothesis that strains with high MNDCM frequency would be better at mounting a proliferative response. This also translated to a greater functional improvement and smaller scars in M520 rats, but not in F344. Additionally, we looked at the size of cardiomyocytes following MI and found that HXB23 rats (20.9% ≥8N CMs) have an increased cross-sectional area in comparison to the other strains, which may be indicative of concentric hypertrophy in response to injury. The HRDP could serve as a powerful tool for mapping traits related to outcomes following MI, allowing us to identify potential gene candidates that may be interrogated further for future use in precision medicine-based therapies. Mapping studies are ongoing.
Abstract P1076: Phosphodiesterase 1 (pde1) Modulates CAMP Signaling At The Sarcolemmal Membrane
Authors: Grace K Muller, Manuela Zaccolo, David A Kass
Journal: Circulation Research (2022)

Phosphodiesterases (PDEs) regulate cyclic nucleotide-mediated cell signaling and offer a therapeutic means to leverage cardiac function. FDA-approved PDE3 inhibitors increase myocyte contractility by enhancing L-type calcium channel activity and sarcoplasmic reticulum (SR) calcium (Ca 2+ ) load, but cause fatal arrhythmias in patients with heart failure. The PDE1 inhibitor ITI-214 is a novel inotrope that increases cardiac contractility in animal models and human patients with heart failure. Mechanistically, PDE1 inhibition leads to activation of the L-type Ca 2+ channel without altering the SR Ca 2+ load or myofilament-Ca 2+ sensitivity. The net result is enhanced myocyte contractility with comparatively less Ca 2+ increase and arrhythmias. PDE inhibition increases cAMP levels to activate protein kinase A (PKA), a pathway that regulates Ca 2+ handling and cycling. These results led us to hypothesize that PDEs 1 and 3 differ in localized domains where each controls cAMP-mediated signaling. Live-cell imaging experiments were performed in acutely isolated guinea pig myocytes expressing Förster resonance energy transfer (FRET) sensors to monitor changes in cAMP levels. These sensors were targeted to specific sarcolemmal domains or more generally to the cytosol. Our results showed that PDE1 inhibition is the predominant regulator of cAMP at the non T-tubular sarcolemmal membrane compared to other cAMP-hydrolyzing PDEs (PDE3 and 4). In contrast to PDE1, PDEs 3 and 4 were more indiscriminate and modulated cAMP in the cytosolic as well as in membrane domains. Upon beta-adrenergic stimulation, however, PDE4 but not PDEs 1 or 3 became the predominant cAMP modulator at the T-tubular membrane domain. These results provide evidence that PDE1 is a major regulator of sarcolemmal membrane cAMP, suggesting that PDE1 inhibitory effects upon the L-type Ca 2+ channel is localized to this domain. In future studies, we will examine if PDE1 inhibition selectively activates PKA in this region, and seek to identify the interacting proteins that support PDE1 modulation of sarcolemmal cAMP/PKA signaling. Resolving this cell signaling difference would provide mechanistic insight into a novel inotrope that has already completed a Phase II clinical evaluation in patients.
Abstract P3054: Alpha-1a Adrenergic Receptor Activation Increases Electron Transport Chain Activity And Preserves Cardiac Contractility Following Myocardial Infarction
Authors: Peyton B Sandroni, Wei Huang, Brian C Jensen
Journal: Circulation Research (2022)

Heart failure features decreased electron transport chain (ETC) activity in cardiomyocyte mitochondria. Previous studies have demonstrated that alpha-1A adrenergic receptor (α1A-AR) activation increases cardiac contractility in the failing heart. However, α1A-AR activation as a method of ETC regulation following cardiac injury has not been studied. Here, we assessed the hypothesis that α1A-AR activation increases ETC activity following myocardial infarction (MI) induced by left coronary artery ligation. We measured cardiac contractility using echocardiography at baseline and 7 days after MI in male CL57Bl/6J mice receiving the selective α1A-AR agonist A61603 (10 ng/kg/d) (n = 8) or vehicle (0.9% saline) (n = 9) via subcutaneous osmotic minipumps (Panel A). We then profiled citrate synthase (CS), a key enzyme in the citric acid cycle and common marker for mitochondrial mass, and ETC Complex I-IV activities in ventricular lysates. ETC enzyme activities were normalized to CS to define ETC capacity on a per mitochondrion basis. On Day 0, there were no differences in fractional shortening between groups (Panel B, 46 ± 3% vs. 49 ± 3%, p = 0.27) (mean ± SEM). On Day 7, fractional shortening was preserved in A6-treated mice compared to vehicle controls (Panel B, 24 ± 3% vs. 14 ± 1%, p = 0.01). A6 decreased CS activity compared to vehicle controls (Panel C, 11,024 ± 1,035 vs. 15,966 ± 1,068 nmol/mg/min, p &lt; 0.01). When normalized to CS activity, A6 increased Complex I (16 ± 2% vs. 7 ± 1%, p &lt; 0.01) (1,584 ± 116 vs. 1,106 ± 154 nmol/min/mg), Complex III (82 ± 8% vs. 56 ± 5%, p = 0.01) (8,435 ± 461 vs. 8,542 ± 327 nmol/min/mg), and Complex IV (121 ± 12% vs. 92 ± 9.%, p = 0.04) (12,523 ± 673 vs. 14,174 ± 1,156) activities (Panel D), suggesting enhanced ETC activity on a per mitochondrion basis. In conclusion, we show that a low dose of a selective α1A-AR agonist enhances cardiac contractility following MI. Increased ETC enzyme activity, particularly Complex I, may contribute to this beneficial effect. Ours is the first study in which selective α1A-AR activation has been linked to enhanced cardiac contractility and mitochondrial metabolism following MI. These findings may outline a novel mechanism through which α1A-AR activation preserves cardiac function in the injured and failing heart.